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Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease

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Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ......................................................................................... 62 4 Recalibration for Validation.................................................................................................................. 63 5 Table of Individual Proteins Associated with Cardiovascular Risk ....................................................... 67 5.1 Biological Functions of 16 LASSO-selected Proteins ................................................................... 74 5.2 9-Protein Model Specification .................................................................................................... 77 6 Risk Score Distributions by Event Type ................................................................................................ 79 7 References ............................................................................................................................................ 80 List of Figures and Tables eTable 1: List of 1130 proteins measured by SomaLogic’s modified aptamer-based proteomic assay. __________ 4 eTable 2: Coefficients for Weibull recalibration model applied to 9-protein model. _________________________ 64 eFigure 1: Median protein levels in Derivation and Validation cohort. ____________________________________ 65 eTable 3: Coefficients for the recalibration model applied to refit Framingham. ___________________________ 66 eFigure 2: Calibration plots for the refit Framingham model. __________________________________________ 666 eTable 4: List of 200 proteins associated with the risk of MI, stroke, heart failure and death. _________________ 67 eFigure 3: Hazard ratios of LASSO selected proteins for primary end-point of MI, stroke, heart failure and death. 76 eFigure 4: 9-protein prognostic model hazard ratios adjusted for Framingham variables. ____________________ 78 eFigure 5: 9-protein risk scores by event type. _______________________________________________________ 79 © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 1 Study Design and Data Processing The flowchart shown in Figure 1 in the main article describes the key steps in the development and validation of the 9-protein model discussed in the main manuscript. Protein measurements in plasma samples were generated over a period of 3 weeks in 32 separate assay runs. Study samples were randomly assigned to assay runs along with a set of calibration and control samples. No identifying information was available to the laboratory technicians operating the assay. Intra-run normalization and inter-run calibration were performed according to assay data quality control (QC) procedures defined in the good laboratory practice (GLP) quality system of SomaLogic, Inc. Inter- run calibration removes “batch effects” between the successive assay runs by matching the median signal over replicate observations of a pooled plasma calibrator sample included in each assay run to a fixed signal level reference. Typical calibration scale factors are close to unity and quality control (QC) acceptance criteria specify the acceptable range of scale factors as the median scale factor ± 40%. Intra- run normalization controls for “bulk” signal intensity biases that can result from either differential hybridization efficiency or differential sample dilution (or other collection protocol artifacts) that change the total protein concentration in the sample. The former effect is captured by a set of controls used to monitor the hybridization reaction for each sample and the latter uses the median of the ratio of median signal levels in each sample to the median signal level for the modified aptamers over all samples within the run. Typical normalization scale factors are close to unity and quality control (QC) acceptance criteria requires normalization scale factors for a sample to fall in the range [0.4, 2.5]. Seventy-six of the original 1130 proteins measured failed the inter-run calibration QC metrics in at least one of the 32 independent assay runs and were considered technical (analytical) failures unfit for analysis. Samples failing the intra- run normalization quality control (QC) metrics were technical failures unfit for analysis. Hemolyzed samples have a distinctive pattern of extreme hemoglobin and haptoglobin levels and extreme signal levels in more than 5% of proteins measured with the modified aptamer platform are indicative of additional sample degradation. Of the 2496 samples that passed the QC metrics, 73 (n=37 derivation, n=36 validation) were deemed unfit for analysis because they were hemolyzed (n=22 derivation, n=26 validation) or had at least 5% of the proteins measured (n=15 derivation, n=10 validation) exceed an outlier threshold defined as the median ± the maximum of 6 median absolute deviations and 5 times the median. © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 2 Table of 1130 Proteins Measured eTable 1 (below): List of 1130 Proteins measured by Somalogic’s modified aptamer-based proteomic assay, Version 3. The 76 proteins that failed quality control metrics were excluded from the analysis are indicated in the fourth column. Excluded from Protein Analyte UniProt ID Gene Analysis sPLA2-Iia 14-3-3 protein family -- -- 14-3-3σ | Stratifin P31947 SFN 15-hydroxyprostaglandin P15428 HPGD dehydrogenase | 15-PGDH | HPG-1 3-hydroxyacyl-CoA dehydrogenase Q99714 HSD17B10 type-2|ABAD | ERAB 3-hydroxyisobutyrate dehydrogenase P31937 HIBADH 4-1BB | CD137 Q07011 TNFRSF9 4-1BB ligand | CD137L P41273 TNFSF9 6Ckine | CCL21 O00585 CCL21 6-Phosphogluconate dehydrogenase P52209 PGD Acid ceramidase-like protein | N- acylethanolamine-hydrolyzing acid Q02083 NAAA amidase | ASAHL Acid phosphatase 1, soluble | Adipocyte acid phosphatase | LMW- P24666 ACP1 PTP Acidic fibroblast growth factor | β- P05230 FGF1 endothelial cell growth factor © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Excluded from Protein Analyte UniProt ID Gene Analysis Acidic leucine-rich nuclear Q92688 ANP32B phosphoprotein 32 family member B Activated leukocyte cell adhesion Q13740 ALCAM molecule | CD166 Activated protein C P04070 PROC Activin A | Inhibin β-A homodimer P08476 INHBA Activin AB | Inhibin β-A:β-B P08476, P09529 INHBA INHBB heterodimer Activin receptor-like kinase 1 | ALK-1 P37023 ACVRL1 Activin serine-threonine-protein P36896 ACVR1B kinase receptor type-1B | ALK-4 ADAM metallopeptidase domain 12 O43184 ADAM12 ADAM metallopeptidase domain 9 Q13443 ADAM9 ADAM metallopeptidase with Q9UHI8 ADAMTS1 thrombospondin motifs 1 ADAM metallopeptidase with Q76LX8 ADAMTS13 thrombospondin motifs 13 ADAM metallopeptidase with Q8TE58 ADAMTS15 thrombospondin motifs 15 ADAM metallopeptidase with thrombospondin motifs 4 | O75173 ADAMTS4 Aggrecanase 1 ADAM metallopeptidase with thrombospondin motifs 5 | Q9UNA0 ADAMTS5 Aggrecanase 2 © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Excluded from Protein Analyte UniProt ID Gene Analysis Adaptor protein Crk-I P46108 CRK Adenylate kinase 1 | Myokinase P00568 AK1 Adenylosuccinate lyase P30566 ADSL Adiponectin Q15848 ADIPOQ Y Adrenocorticotropic hormone P01189 POMC Y Afamin P43652 AFM Aflatoxin B1 aldehyde reductase O43488 AKR7A2 Aggrecan core protein P16112 ACAN Agouti-related protein O00253 AGRP AITRL | Activation-induced TNFR member Ligand | GITRL | Q9UNG2 TNFSF18 Glucocorticoid-induced TNF receptor ligand Albumin P02768 ALB Alcohol dehydrogenase (NADP+) | Aldo-keto reductase family 1 member P14550 AKR1A1 A1 Alkaline phosphatase, tissue- P05186 ALPL nonspecific isozyme Alkaline sphingomyelinase Q6UWV6 ENPP7 Allograft inflammatory factor 1 P55008 AIF1 Aminoacylase-1 Q03154 ACY1 Amnionless Q9BXJ7 AMN Y AMP kinase (α1β1γ1) Q13131, Q9Y478, P54619 PRKAA1 PRKAB1 PRKAG1 AMP kinase (α2β2γ1) P54646, O43741, P54619 PRKAA2 PRKAB2 PRKAG1 Amphiregulin P15514 AREG © 2016 American Medical Association. 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